Molecular analysis of enthesopathy in a mouse model of hypophosphatemic rickets

Development. 2018 Aug 10;145(15):dev163519. doi: 10.1242/dev.163519.


The bone tendon attachment site known as the enthesis comprises a transitional zone between bone and tendon, and plays an important role in enabling movement at this site. X-linked hypophosphatemia (XLH) is characterized by impaired activation of vitamin D, elevated serum FGF23 levels and low serum phosphate levels, which impair bone mineralization. Paradoxically, an important complication of XLH is mineralization of the enthesis (enthesopathy). Studies were undertaken to identify the cellular and molecular pathways important for normal post-natal enthesis maturation and to examine their role during the development of enthesopathy in mice with XLH (Hyp). The Achilles tendon entheses of Hyp mice demonstrate an expansion of hypertrophic-appearing chondrogenic cells by P14. Post-natally, cells in wild-type and Hyp entheses similarly descend from scleraxis- and Sox9-expressing progenitors; however, Hyp entheses exhibit an expansion of Sox9-expressing cells, and enhanced BMP and IHH signaling. These results support a role for enhanced BMP and IHH signaling in the development of enthesopathy in XLH.

Keywords: 1,25 dihydroxyvitamin D; BMP; Enthesis; FGF23; IHH; Phosphate; Tendon-bone attachment; XLH.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alkaline Phosphatase / metabolism
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Bone Morphogenetic Proteins / metabolism
  • Cell Proliferation / drug effects
  • Chondrogenesis / drug effects
  • Disease Models, Animal
  • Enthesopathy / complications*
  • Enthesopathy / drug therapy
  • Enthesopathy / genetics*
  • Enthesopathy / pathology
  • Female
  • Fibroblast Growth Factors / pharmacology
  • Fibroblast Growth Factors / therapeutic use
  • Hedgehog Proteins / metabolism
  • Male
  • Mice, Inbred C57BL
  • Rickets, Hypophosphatemic / complications*
  • Rickets, Hypophosphatemic / drug therapy
  • Rickets, Hypophosphatemic / genetics*
  • Rickets, Hypophosphatemic / pathology
  • SOX9 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Stem Cells / drug effects
  • Stem Cells / metabolism
  • Vitamin D / analogs & derivatives
  • Vitamin D / pharmacology
  • Vitamin D / therapeutic use


  • Basic Helix-Loop-Helix Transcription Factors
  • Bone Morphogenetic Proteins
  • Hedgehog Proteins
  • SOX9 Transcription Factor
  • Scx protein, mouse
  • ihh protein, mouse
  • Vitamin D
  • Fibroblast Growth Factors
  • 1,25-dihydroxyvitamin D
  • fibroblast growth factor 23
  • Alkaline Phosphatase